Slow Growth and Dormancy in Bacteria (renewal)

Increasing attention has been focused on the growing problem of antibiotic resistance. It is estimated that there are approximately 1.3 million deaths per year due to bacterial infections that cannot be effectively treated with the antibiotics we have relied on in the past, because the bacteria have become resistant to them and can continue to grow in their presence.

This problem is expected to become worse. However, currently, many more people die from infections caused by bacteria that are considered sensitive to antibiotics than from infections due to antibiotic-resistant bacteria. These infections usually affect people whose immune system is compromised in some way.

The bacteria causing the infection are sensitive to the antibiotics being used when they are tested in the laboratory under ideal conditions, but the antibiotics still fail to clear the infection, leading to chronic or recurrent disease. The bacteria manage to tolerate exposure to the antibiotic, even though they cannot grow in its presence. It appears that stresses the bacteria experience in infections can cause them to stop growing, which increases their ability to tolerate antibiotics, because most antibiotics target processes that are associated with growth.

The problems of antibiotic tolerance and antibiotic resistance are related: tolerance can serve as a stepping stone to resistance. Bacteria that survive exposure to an antibiotic by adopting a low-activity, antibiotic-tolerant state have opportunities to acquire mutations that confer resistance to that antibiotic and allow them to continue growing if they are exposed to the same antibiotic again.

It is urgent that we develop new antibiotics, but progress in this area has faltered. The research described here will specifically focus on developing new therapies to target antibiotic-tolerant bacteria. We have worked to improve our understanding of how bacteria tolerate antibiotics, by studying the processes they rely on when they are not actively growing due to a stress that they are likely to encounter in an infection.

We have identified distinct pathways that are more important during growth arrest. We are now working to find compounds that can kill bacteria while they are exposed to an infection-relevant stress, and while they are successfully tolerating a standard antibiotic. We will apply this strategy to finding treatments for antibiotic-tolerant Escherichia coli under conditions they might encounter in a urinary tract infection.

Meanwhile, we will also develop strategies to determine exactly how compounds that are successful in our screen are able to kill the bacteria. We will first develop these strategies for compounds that kill the bacterium Pseudomonas aeruginosa under conditions that mimic lung infections, and we will use the basic research we have done on the pathways important for growth arrest in this organism to interpret the results.

We will then adapt the strategy to the new compounds we find that work against E. coli. For the most successful new compounds, we will seek further funding to develop them into drug candidates. We hope that our model of (1) screening compounds against bacteria that are in a state that closely mimics the infection; then (2) seeking to deeply understand the biological reason why the compounds work, can help stimulate progress in finding new types of antibiotics that are more successful in clearing chronic infections.